A cooperative water effect in proazaphosphatranecatalysed heterocycle synthesis

The synthesis of oxazolines and imidazolines was achieved by activation of isocyanides with water. Mechanistic studies show that the organosuperbase proazaphosphatrane is tolerant of water within the reaction medium, with a beneficial and cooperative effect being observed

Conditioning with spatio-temporal patterns: Constraining the contribution of the hippocampus to configural learning

The conditions under which the hippocampus contributes to learning about spatio-temporal configural patterns are not fully established. The aim of Experiments 1–4 was to investigate the impact of hippocampal lesions on learning about where or when a reinforcer would be delivered. In each experiment, the rats received exposure to an identical set of patterns (i.e., spotted + morning, checked + morning, spotted + afternoon and checked + afternoon); and the contexts (Experiment 1), times of day (Experiment 2), or their configuration (Experiments 3 and 4) signalled whether or not a reinforcer would be delivered. The fact that hippocampal damage did not disrupt the formation of simple or configural associations involving spatio-temporal patterns is surprising, and suggests that the contribution of the hippocampus is restricted to mediated learning (or updating) involving spatio-temporal configurations

Hippocampal lesions disrupt an associative mismatch process

Novel assays were used to assess inter alia whether the hippocampus is involved in detecting novelty per se or in an associative mismatch process. During training, rats received two audiovisual sequences (tone–left constant light and click– left flashing light). In both sham-operated control rats and those with excitotoxic hippocampal lesions, novel visual targets provoked an orienting response that habituated during training. Moreover, like sham-operated rats, rats with hippocampal lesions acquired associations between the elements of two audiovisual sequences. However, subsequent test trials in which the auditory stimuli preceding the visual targets were switched (click–left constant light and tone–left flashing light) provoked renewed orienting to the visual targets in sham-operated rats but not in hippocampal rats. These results support the view that hippocampal damage results in a failure to detect (or act on) mismatches that are generated when an auditory stimulus associatively evokes the memory of one visual stimulus and a different (familiar) visual stimulus is present in the environment

Decarboxylative bromination of heteroarenes: initial mechanistic insights

After an initial report from our laboratory describing metal-free decarboxylative halogenation of various azaheteroarenes, we set out to investigate the possible mechanism by which this chemistry occurs. Evidence from this mechanistic investigation suggests that this chemistry occurs via a radical pathway, with 1HNMR studies suggesting the acidic substrates activate NBS

Metal-free selective mono-halodecarboxylation of heteroarenes under mild conditions

The halodecarboxylation of heteroarene carboxylic acids by treatment with N-bromosuccinimide or N-chlorosuccinimide was performed. This procedure provides a convenient route to synthetically useful mono-halogenated heteroarene intermediates such as halo-indoles, -aza-indoles, -indazoles and -aza-indazoles. The mild conditions employed and simple protocol provides an advantage over traditional halodecarboxylation procedures that require expensive and toxic metal catalysts, basic conditions, time-consuming intermediate isolation and elevated reaction temperatures

2,8-Disubstituted-1,6-Naphthyridines and 4,6-Disubstituted-Isoquinolines with Potent, Selective Affinity for CDK8/19

We demonstrate a designed scaffold-hop approach to the discovery of 2,8-disubstituted-1,6-naphthyridine- and 4,6-disubstituted-isoquinoline-based dual CDK8/19 ligands. Optimized compounds in both series exhibited rapid aldehyde oxidase-mediated metabolism, which could be abrogated by introduction of an amino substituent at C5 of the 1,6-naphthyridine scaffold or at C1 of the isoquinoline scaffold. Compounds 51 and 59 were progressed to in vivo pharmacokinetic studies, and 51 also demonstrated sustained inhibition of STAT1SER727 phosphorylation, a biomarker of CDK8 inhibition, in an SW620 colorectal carcinoma human tumor xenograft model following oral dosing

Maturation of heterogeneity in afferent synapse ultrastructure in the mouse cochlea

Auditory nerve fibers (ANFs) innervating the same inner hair cell (IHC) may have identical frequency tuning but different sound response properties. In cat and guinea pig, ANF response properties correlate with afferent synapse morphology and position on the IHC, suggesting a causal structure-function relationship. In mice, this relationship has not been fully characterized. Here we measured the emergence of synaptic morphological heterogeneities during maturation of the C57BL/6J mouse cochlea by comparing postnatal day 17 (p17, ∼3 days after hearing onset) with p34, when the mouse cochlea is mature. Using serial block face scanning electron microscopy and three-dimensional reconstruction we measured the size, shape, vesicle content, and position of 70 ribbon synapses from the mid-cochlea. Several features matured over late postnatal development. From p17 to p34, presynaptic densities (PDs) and post-synaptic densities (PSDs) became smaller on average (PDs: 0.75 to 0.33; PSDs: 0.58 to 0.31 μ

A rapidly acquired foraging-based working memory task, sensitive to hippocampal lesions, reveals age-dependent and age-independent behavioural changes in a mouse model of amyloid pathology

© 2018 Elsevier Inc. Three experiments examined the ability of mice to forage efficiently for liquid rewards in pots located in an open field arena. Search behaviour was unconstrained other than by the walls of the arena. All mice acquired the task within 4 days of training, with one trial per day. Experiment 1 tested the hypothesis that hippocampal lesions would disrupt foraging behaviour using extramaze cues. Mice with hippocampal lesions showed normal latency to initiate foraging and to complete the task relative to sham-operated mice. However, lesioned mice showed increased perseverative responding (sensitization) to recently rewarded locations, increased total working memory errors and an increased propensity to search near previously rewarded locations. In Experiment 2, the extramaze cues were obscured and each pot was identified by a unique pattern. Under these conditions, mice with hippocampal lesions showed comparable working memory errors to control mice. However, lesioned mice continued to display increased perseverative responding and altered search strategies. Experiment 3 tested the hypothesis that age-related accumulation of amyloid would disrupt foraging behaviour in transgenic PDAPP mice expressing the V717F amyloid precursor protein (APP) mutation. Consistent with previous findings, PDAPP mice showed both age-dependent and age-independent behavioural changes. More specifically, 14–16 month-old PDAPP mice showed a deficit in perseverative responding and working memory errors. In contrast, changes in search behaviour, such as systematic circling, were present throughout development. The latter indicates that APP overexpression contributed to some features of the PDAPP behavioural phenotype, whereas working memory and flexible responding was sensitive to ageing and β-amyloid burden. In conclusion, the present study provided novel insight into the role of the hippocampus and the effects of APP overexpression on memory and search behaviour in an open-field foraging task

Nebulized Recombinant Tissue Plasminogen Activator (rt-PA) for Acute COVID-19-Induced Respiratory Failure : An Exploratory Proof-of-Concept Trial

Acknowledgments We would like to extend our sincerest gratitude to all the colleagues and hospital staff who worked tirelessly throughout the pandemic and without whom this work would not have been possible. Firstly, we would like to thank our colleagues in the intensive care unit (ICU), in particular the matrons, Sean Carroll and Sinead Hanton, and research nurses, Filipe Helder and Amitaa Maharajh for their support, and bedside nurses who bore the responsibility of drug administration. We would also like to extend our thanks to ICU consultants who acted as professional legal consultees on behalf of critical care patients. Equally, we would like to thank colleagues within the respiratory team. Their expertise was instrumental to our role in treating patients on 8N and 8E wards. A special mention to lead Nurse Mary Emerson; we were grateful for her knowledge, support and for facilitating the training for the nebulizer and drug administration on the wards. We would like to thank Aarti Nandani and all the staff in the Royal Free clinical trials pharmacy for their immense support throughout the whole pandemic, especially considering their ever-increasing workload at the time. Thanks also to the HSL coagulation laboratory, the Trust R&D department and all the staff working to cover during a very challenging time. We are also very grateful to the Royal Free charity for funding this study. Finally, we would like to thank all the clinical nurses, physiotherapists, research data managers and healthcare professionals within the Haemophilia department (and wider hospital) for all their many efforts in supporting this study. This trial was overseen by an independent data monitoring committee, chaired by Najib Rahman, Director of the Oxford Respiratory Trials Unit, University of Oxford and comprises the following committee members: Mike Makris, Jonathan Silversides and Henry Watson. Funding Royal Free Charity Trust Fund 35 provided funding for this study. The study drug was provided by Boehringer Ingelheim (BI). BI had no role in the design, analysis, or interpretation of the results. They were given the opportunity to review the manuscript for medical and scientific accuracy since it relates to BI substances and intellectual property considerations.Peer reviewedPublisher PD